1. Field of the Invention
The present invention relates to processes for preparing alkyl(methoxymethyl)trimethylsilanylmethylamines.
2. Background Art
The literature describes the syntheses of various alkyl(methoxymethyl)trimethylsilanylmethylamines of the general formula (A).

The R radical may be defined, for example, as benzyl, tert-butyl, 2-vinylbenzyl, isopropyl, 2-hydroxy-2-phenylethanoyl, 4-nonylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl, allyl, 3-pyridinylmethyl, (R)- and (S)-1-phenylethyl, (S)-1-naphthylethyl, or cyclohexyl.
Alkyl(methoxymethyl)trimethylsilanylmethylamines are used as building blocks for preparing pyrrolidines. In this case, the compounds detailed above are converted in the presence of strong acids, for example trifluoroacetic acid, or Lewis acids such as lithium fluoride, to azomethinylides, which can then react stereoselectively with alkenes by means of 3+2 cycloaddition (reaction scheme (I)) (Review article: A. Padwa, W. Dent, J. ORG. CHEM. 1987, 52, 235-244.).

The literature describes two fundamentally different access routes to alkyl(methoxymethyl)trimethylsilanylmethylamines.
WO2000015611 describes a process for preparation proceeding from alkyltrimethylsilanylmethylamines. Deprotonation with a strong base, for example n-butyllithium, converts the compound to the corresponding amide (reaction equation (II)). This is subsequently reacted with chloromethyl methyl ether in a substitution reaction to give the desired target compound. This synthesis has the crucial disadvantage that chloromethyl ethers are highly carcinogenic.

Another means of preparing alkyl(methoxymethyl)trimethylsilanylmethylamines described many times in the literature is the reaction of alkyltrimethylsilanylmethylamines with aqueous formaldehyde solution and methanol in the presence of a base, according to reaction scheme (III).

The isolated yields for the different compounds are within the range of 49 and 88%. Often, the target compound is also isolated only as a crude compound and is converted further in situ. In the syntheses, between 1.8 and 56 equivalents of methanol (based on the corresponding alkyltrimethylsilanylmethylamine) and between 1.0 and 2.9 equivalents of formaldehyde (based on the corresponding alkyltrimethylsilanylmethylamine) are used. The formaldehyde is used in the form of an aqueous solution in concentrations between 30 and 38% by weight. The base used is predominantly K2CO3 (0.04 to 1.2 equivalents); in some cases, NaOH is also used (0.17 to 1.36 equivalents). The reactions are conducted at temperatures around 0° C.
P. Kotian et. al. (ORG. PROCESS RES. DEV. 2005, 9, 193-197), describe the preparation of benzyl(methoxymethyl)trimethylsilanylmethylamines by means of the above-described synthesis. In purifying the benzyl(methoxymethyl)trimethylsilanylmethylamines by distillation on a large scale (batch size 9.14 mol of benzyl-trimethylsilanylmethylamine), however, the product decomposes.
WO-2003062252 and WO-2003061567 both describe, in the examples, identical processes for preparing nonylbenzyl(methoxymethyl)-trimethylsilanylmethylamine. Instead of an aqueous formaldehyde solution, in both cases, paraformaldehyde (2.13 equivalents) is used as the formaldehyde source. The base employed is solid NaOH (0.17 equivalent). In these methods, the target product is not isolated further, but rather processed directly from the crude product, without downstream distillation, which would entail the known problems. Paraformaldehyde is not added in an equimolar amount in the process described.
The literature processes which use an aqueous formaldehyde solution as the formaldehyde source all have the disadvantage that they can be converted to a larger scale only with great problems owing to thermal instabilities. In the processes with paraformaldehyde, the prior art does not suggest any means as to how workup problems can be eliminated.